Kinetic studies of HIV-1 and HIV-2 envelope glycoprotein-mediated fusion

BACKGROUND: HIV envelope glycoprotein (Env)-mediated fusion is driven by the concerted coalescence of the HIV gp41 N-helical and C-helical regions, which results in the formation of 6 helix bundles. Kinetics of HIV Env-mediated fusion is an important determinant of sensitivity to entry inhibitors and antibodies. However, the parameters that govern the HIV Env fusion cascade have yet to be fully elucidated. We address this issue by comparing the kinetics HIV-1(IIIB )Env with those mediated by HIV-2 from two strains with different affinities for CD4 and CXCR4. RESULTS: HIV-1 and HIV-2 Env-mediated cell fusion occurred with half times of about 60 and 30 min, respectively. Binding experiments of soluble HIV gp120 proteins to CD4 and co-receptor did not correlate with the differences in kinetics of fusion mediated by the three different HIV Envs. However, escape from inhibition by reagents that block gp120-CD4 binding, CD4-induced CXCR4 binding and 6-helix bundle formation, respectively, indicated large difference between HIV-1 and HIV-2 envelope glycoproteins in their CD4-induced rates of engagement with CXCR4. CONCLUSION: The HIV-2 Env proteins studied here exhibited a significantly reduced window of time between the engagement of gp120 with CD4 and exposure of the CXCR4 binding site on gp120 as compared with HIV-1(IIIB )Env. The efficiency with which HIV-2 Env undergoes this CD4-induced conformational change is the major cause of the relatively rapid rate of HIV-2 Env mediated-fusion

The mPEG-PCL Copolymer for Selective Fermentation of Staphylococcus lugdunensis Against Candida parapsilosis in the Human Microbiome.

Many human skin diseases, such as seborrheic dermatitis, potentially occur due to the over-growth of fungi. It remains a challenge to develop fungicides with a lower risk of generating resistant fungi and non-specifically killing commensal microbes. Our probiotic approaches using a selective fermentation initiator of skin commensal bacteria, fermentation metabolites or their derivatives provide novel therapeutics to rein in the over-growth of fungi. Staphylococcus lugdunensis (S. lugdunensis) bacteria and Candida parapsilosis (C. parapsilosis) fungi coexist in the scalp microbiome. S. lugdunensis interfered with the growth of C. parapsilosis via fermentation. A methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) copolymer functioned as a selective fermentation initiator of S. lugdunensis, selectively triggering the S. lugdunensis fermentation to produce acetic and isovaleric acids. The acetic acid and its pro-drug diethyleneglycol diacetate (Ac-DEG-Ac) effectively suppressed the growth of C. parapsilosis in vitro and impeded the fungal expansion in the human dandruff. We demonstrate for the first time that S. lugdunensis is a skin probiotic bacterium that can exploit mPEG-PCL to yield fungicidal short-chain fatty acids (SCFAs). The concept of bacterial fermentation as a part of skin immunity to re-balance the dysbiotic microbiome warrants a novel avenue for studying the probiotic function of the skin microbiome in promoting health

A gender difference in false recall of negative words: Women DRM more than men

Gender differences in susceptibility to associative memory illusions in the Deese/Roediger-McDermott paradigm were investigated using negative and neutral word lists. Women (n = 50) and men (n = 50) studied 20 lists of 12 words that were associates of a nonpresented critical lure. Ten lists were associates of negatively-valenced lures (e.g., cry, evil) and ten were associates of neutral lures (e.g., chair, slow). When asked to recall the words after each list, women falsely recalled more negative lures than men, but there was no gender difference in the false recall of neutral lures. These findings suggest that women reflect on associations within negative lists to a greater degree than men and are thereby more likely to generate the negative critical lures

The roles of encoding and retrieval processes in associative and categorical memory illusions

Four experiments investigated the origin of associative and categorical memory illusions by comparing the effects of study and test associations on Deese/Roediger-McDermott (DRM) and categorized lists. Experiments 1 and 2 found that levels of false recognition with both list types were increased by manipulations that facilitated the generation of associates at study (blocked presentation of study lists and explicit instructions to generate associates of studied items). Experiments 3 and 4 showed that manipulations designed to increase test associations (test-induced priming and part-set cuing) did not increase levels of false memory with either list type. These findings indicate that false memories produced by both DRM and categorized lists are influenced by associations activated at study but not by associations activated at test

Injury Rates in Age-Only Versus Age-and-Weight Playing Standard Conditions in American Youth Football

BACKGROUND: American youth football leagues are typically structured using either age-only (AO) or age-and-weight (AW) playing standard conditions. These playing standard conditions group players by age in the former condition and by a combination of age and weight in the latter condition. However, no study has systematically compared injury risk between these 2 playing standards. PURPOSE: To compare injury rates between youth tackle football players in the AO and AW playing standard conditions. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Athletic trainers evaluated and recorded injuries at each practice and game during the 2012 and 2013 football seasons. Players (age, 5-14 years) were drawn from 13 recreational leagues across 6 states. The sample included 4092 athlete-seasons (AW, 2065; AO, 2027) from 210 teams (AW, 106; O, 104). Injury rate ratios (RRs) with 95% CIs were used to compare the playing standard conditions. Multivariate Poisson regression was used to estimate RRs adjusted for residual effects of age and clustering by team and league. There were 4 endpoints of interest: (1) any injury, (2) non-time loss (NTL) injuries only, (3) time loss (TL) injuries only, and (4) concussions only. RESULTS: Over 2 seasons, the cohort accumulated 1475 injuries and 142,536 athlete-exposures (AEs). The most common injuries were contusions (34.4%), ligament sprains (16.3%), concussions (9.6%), and muscle strains (7.8%). The overall injury rate for both playing standard conditions combined was 10.3 per 1000 AEs (95% CI, 9.8-10.9). The TL injury, NTL injury, and concussion rates in both playing standard conditions combined were 3.1, 7.2, and 1.0 per 1000 AEs, respectively. In multivariate Poisson regression models controlling for age, team, and league, no differences were found between playing standard conditions in the overall injury rate (RRoverall, 1.1; 95% CI, 0.4-2.6). Rates for the other 3 endpoints were also similar (RRNTL, 1.1 [95% CI, 0.4-3.0]; RRTL, 0.9 [95% CI, 0.4-1.9]; RRconcussion, 0.6 [95% CI, 0.3-1.4]). CONCLUSION: For the injury endpoints examined in this study, the injury rates were similar in the AO and AW playing standards. Future research should examine other policies, rules, and behavioral factors that may affect injury risk within youth football

Formaldehyde 2% is not a useful means of detecting allergy to formaldehyde releasers- results of theESSCAnetwork, 2015-2018

BACKGROUND Studies suggest that patch testing with formaldehyde releasers (FRs) gives significant additional information to formaldehyde 1% aq. and should be considered for addition to the European baseline series (EBS). It is not known if this is also true for formaldehyde 2% aq. OBJECTIVES To determine the frequency of sensitization to formaldehyde 2% aq. and co-reactivity with FRs. To establish whether there is justification for including FRs in the EBS. MATERIALS AND METHODS A 4-year, multi-center retrospective analysis of patients with positive patch test reactions to formaldehyde 2% aq. and five FRs. RESULTS A maximum of 15 067 patients were tested to formaldehyde 2% aq. and at least one FR. The percentage of isolated reactions to FR, without co-reactivity to, formaldehyde 2% aq. for each FR were: 46.8% for quarternium-15 1% pet.; 67.4% imidazolidinyl urea 2% pet.; 64% diazolidinyl urea 2% pet.; 83.3% 1,3-dimethylol-5, 5-dimethyl hydantoin (DMDM) hydantoin 2% pet. and 96.3% 2-bromo-2-nitropropane-1,3-diol 0.5% pet. This demonstrates that co-reactivity varies between FRs and formaldehyde, from being virtually non-existent in 2-bromo-2-nitropropane-1,3-diol 0.5% pet. (Cohen's kappa: 0, 95% confidence interval [CI] -0.02 to 0.02)], to only weak concordance for quaternium-15 [Cohen's kappa: 0.22, 95%CI 0.16 to 0.28)], where Cohen's kappa value of 1 would indicate full concordance. CONCLUSIONS Formaldehyde 2% aq. is an inadequate screen for contact allergy to the formaldehyde releasers, which should be considered for inclusion in any series dependant on the frequency of reactions to and relevance of each individual allergen

The INTEGRAL/IBIS AGN catalogue I: X-ray absorption properties versus optical classification

In this work we present the most comprehensive INTEGRAL AGN sample which lists 272 objects. Here we mainly use this sample to study the absorption properties of active galaxies, to probe new AGN classes and to test the AGN unification scheme. We find that half (48%) of the sample is absorbed while the fraction of Compton thick AGN is small (~7%). In line with our previous analysis, we have however shown that when the bias towards heavily absorbed objects which are lost if weak and at large distance is removed, as it is possible in the local Universe, the above fractions increase to become 80% and 17%. We also find that absorption is a function of source luminosity, which implies some evolution in the obscuration properties of AGN. Few peculiar classes, so far poorly studied in the hard X-ray band, have been detected and studied for the first time such as 5 XBONG, 5 type 2 QSOs and 11 LINERs. In terms of optical classification, our sample contains 57% of type 1 and 43% of type 2 AGN; this subdivision is similar to that found in X-rays if unabsorbed versus absorbed objects are considered, suggesting that the match between optical and X-ray classification is overall good. Only a small percentage of sources (12%) does not fulfill the expectation of the unified theory as we find 22 type 1 AGN which are absorbed and 10 type 2 AGN which are unabsorbed. Studying in depth these outliers we found that most of the absorbed type 1 AGN have X-ray spectra characterized by either complex or warm/ionized absorption more likely due to ionized gas located in an accretion disk wind or in the biconical structure associated to the central nucleus, therefore unrelated to the toroidal structure. Among 10 type 2 AGN which resulted to be unabsorbed, at most 3-4% is still eligible to be classified as a "true" type 2 AGN.Comment: 21 pages, 6 figures, 5 tables. Accepted for publication on MNRAS. arXiv admin note: text overlap with arXiv:0709.2077 by other author

Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma.

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole-genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of nonsynonymous single-nucleotide variants being shared in diagnostic-recurrent pairs. To track the origins of the mutational events observed in pGBM, we generated whole-genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to nondividing cells. Interestingly, radiation and antimitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, because slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and therefore would accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM. SIGNIFICANCE: This work challenges several assumptions regarding the genetic organization of pediatric GBM and highlights mutagenic programs that start during early prenatal development.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/9/2111/F1.large.jpg.Wellcome Trust Royal Societ